KR20010020808A - New substituted pyridine or piperidine compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

PURPOSE: A compound is provide which exhibits an analgesic characteristic and a characteristic promoting recognizing process and useful for treatment of pain and treatment of aging of brain and amnesia accompanying neurodegeneration diseases such as Alzheimer's disease, Parkinson's disease and Pick disease. CONSTITUTION: The compound is represented by formula I (A is pyridine or the like; R3 is hydroxy for the like; R4 is phenyl or the like; R1 is H or the like; R5 is a 5-6 membered heterocycle which may contain a nitrogen atom binding to the ring A and may contain another hetero atom selected from sulfur, oxygen and nitrogen; R6 is H or the like), e.g. 1-(4-bromophenyl)-2-(1-methyl-2- piperidinyl)-1-ethanone. The compound of formula I is obtained by reacting, e.g. a compound obtained by alkylating a compound of formula II (X is H or fluorine) with an alkylating agent with a compound of formula III (Ra and Rb form a 5 to 6-membered heterocycle which may contain another hetero atom selected from sulfur, oxygen or nitrogen together with nitrogen binding to these groups; Rc is H or the like).

Description

Substituted pyridine or piperidine compounds, methods for their preparation, and pharmaceutical compositions containing them {NEW SUBSTITUTED PYRIDINE OR PIPERIDINE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM}

The present invention relates to novel substituted pyridine or piperidine compounds, methods for their preparation, pharmaceutical compositions containing them, and their use as memory and cognitive enhancers and analgesics.

Due to the increased life expectancy, aging of the population has resulted in a marked increase in cognitive diseases associated with normal brain aging and pathological brain aging that occur during the course of neurodegenerative diseases such as, for example, Alzheimer's disease.

Most of the substances used today to treat cognitive disorders associated with aging are central cholinergic systems—directly in the case of acetylcholinesterase inhibitors (tacrine, donenephenyl) and cholinergic antagonists (nepyracetam), or indirectly nontropic drugs. (Piracetam, pramiracetam) and cerebral vasodilators (vinpocetin)-act to promote.

In addition to these cognitive properties, substances that directly act on the central cholinergic system mainly have analgesic properties, but also have undesirable hypothermic properties.

Thus, it has been particularly valuable to synthesize novel compounds that can inhibit cognitive diseases associated with aging and / or enhance cognitive action and can have analgesic properties without hypothermic activity.

There is a document in which substituted piperidine compounds are described as synthetic and / or alkaloid products (J. Chem. Soc., Perkin Trans. 1, 1991, (3), pp. 611-616; Heterocycles, 1985, 23 (4), pp. 831-834; Can. J. Chem., 1996, 74 (12), pp. 2444-2453).

Substituted pyridine compounds are also described in their synthesis (J. Chem. Soc., Dalton Trans., 1998, (6), pp. 917-922) or in their interactions in metal complexes (J. Chem. Soc., Chem. Commun., 1987, (19), pp. 1457-1459; J. Am. Chem. Soc., 1985, 107 (4), pp. 917-925).

The compounds of the present invention are novel and have particularly valuable properties from a pharmacological point of view.

More specifically, the present invention relates to compounds of formula (I), enantiomers, diastereomers thereof, and addition salts with pharmaceutically acceptable acids or bases:

Where

A is a pyridine group, a pyridinium group or a piperidine group,

R ₂ is a hydrogen atom, R ₃ is a hydroxy group, or R ₂ and R ₃ together form an oxo group,

R ₄ is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted heteroaryl group,

R ₁ is a hydrogen atom, or R ₁ and R ₄ together with two carbon atoms form a ring of 6 carbon atoms, or R ₁ and R ₂ form an additional bond, in which case R ₃ represents a heterocycle A 5- or 6-membered heterocycle containing nitrogen atoms to which it is bound and which may contain another hetero atom selected from sulfur, oxygen and nitrogen,

R ₅ is a 5- or 6-membered heterocyclic ring of formula (II) which contains a nitrogen atom which binds the hetero ring to ring A and may contain another hetero atom selected from sulfur, oxygen and nitrogen (Wherein R ' ₁ , R' ₂ , R ' ₃ and R' ₄ may be the same as R ₁ , R ₂ , R ₃ and R ₄ , respectively) or a hydrogen atom and R ₅ is hydrogen, ₄ may not be an unsubstituted phenyl group, an unsubstituted naphthyl group or a heteroaryl group,

R ₆ is a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group, R ₆ is present or absent depending on the nature of the ring A,

Heteroaryl is understood to represent aromatic monocyclic or bicyclic 5- to 10-membered groups containing 1-3 heteroatoms selected from oxygen, nitrogen and sulfur,

The term "substituted" as used for "phenyl", "naphthyl" or "heteroaryl", refers to a linear or branched (C ₁ -C ₆ ) alkyl, linear or branched (C ₁ -C ₆ ) group. Same or selected from alkoxy, mercapto, linear or branched (C ₁ -C ₆ ) alkylthio, amino, linear or branched (C ₁ -C ₆ ) alkylamino, di- (C ₁ -C ₆ ) alkylamino It is understood that it may be substituted by one or more groups which may be different, wherein each alkyl moiety is a linear or branched (C ₁ -C ₆ ) polyhaloalkyl, hydroxy or halogen atom;

When R ₂ and R ₃ together form an oxo group, R ₅ is a hydrogen atom, R ₆ is a hydrogen atom or absent, and R ₄ is hydroxy, alkoxy, CF ₃ and halogen (if A is a piperidine group) , Bromine is excluded) or a group other than a phenyl group substituted by one group selected from hydroxy and alkoxy,

When R ₂ is a hydrogen atom, R ₃ is a hydroxy group, R ₅ is a hydrogen atom, R ₆ is a hydrogen atom or absent, R ₄ is hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, Groups other than linear or branched (C ₁ -C ₆ ) alkyl and phenyl groups substituted by one group selected from chlorine or substituted by several groups selected from hydroxy and alkoxy,

The compound of formula (I) may not be 1- (1,3-benzodioxol-5-yl) -2- (2-pyridinyl) ethanol or 2- (2-pyridinyl) cyclohexanone.

Pharmaceutically acceptable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid Acids, methanesulfonic acid, camphor acid, oxalic acid and the like can be mentioned, but are not limited to these.

Pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tertiary butylamine, and the like.

Preferred compounds of the invention are compounds of formula (I), wherein Is a pyridinyl group, an N-methylpyridinium group, a piperidinyl group, or an N-methylpiperidinyl group.

Preferred substituents R ₄ are phenyl groups or substituted phenyl groups, in particular phenyl groups substituted by halogen atoms, preferably bromine atoms.

Advantageously, the invention is a compound of formula (I), wherein R ₅ is a hydrogen atom or a group of formula (II).

Preferred groups R ₂ and R ₃ are those in which R ₂ and R ₃ together form an oxo group, R ₂ is a hydrogen atom, and R ₃ is a hydroxy group.

More advantageously, the present invention relates to compounds of formula (I)

1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol,

(R) -1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanone,

(S) -1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanone,

1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol,

(S, S) -1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol,

(R, R) -1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol,

1-methyl-2- [2-oxo-2- (4-bromophenyl) ethyl] pyridinium iodide.

Enantiomers, diastereoisomers and addition salts with pharmaceutically acceptable acids or bases of preferred compounds of the invention form an integral part of the invention.

The present invention also relates to a process for the preparation of the compound of formula (I), for example alkyl para-toluenesulfonate or alkyl trifluoromethanesulfonate using the compound of formula (III) as starting material Alkylation with an alkylating agent such as affords compounds of formula (IV);

The compound of formula (IV) is reacted with one or two compounds of formula (V) which may be the same or different to give a compound of formula (I / a) which is a specific form of the compound of formula (I) Can do it;

Compounds of formula (I / a) can be treated with hydrochloric acid such as HCl, HBr or HI or ammonium salts such as NH ₄ ⁺ PF ₆ ^- to give compounds of formula (I / a ');

The compound of formula (I / a ') may be hydrolyzed with concentrated hydrochloric acid solution to obtain a compound of formula (I / b), which is a specific form of the compound of formula (I);

The compounds of formulas (I / a), (I / a ') and (I / b) constitute compounds of formula (I / c), which are certain forms of compounds of formula (I);

Converting the compound of formula (I / c) to the corresponding iodide salt by the action of NaI to obtain a compound of formula (I / d), which is a specific form of the compound of formula (I);

Compounds of formula (I / d) can be subjected to, for example, catalytic hydrogenation on platinum oxide to give compounds of formula (I / e) which are specific forms of compounds of formula (I), or to pyridinium salts. Treating to obtain a compound of formula (I / f) which is a specific form of a compound of formula (I);

Hydrogenating the obtained compound by a catalytic hydrogenation reaction to obtain a compound of formula (I / g) which is a specific form of the compound of formula (I);

Compounds of formulas (I / b) and (I / c) to (I / g), wherein R _2a and R _3a together form an oxo group, are treated with a reducing agent such as, for example, NaBH ₄ , It is possible to obtain the following general formula (I / h), which is a specific form of the compound of I);

Compounds of formula (I / h) may be selected from (R, R)-(-) or (S, S)-(+)-N, N'-bis (3,5-di-tert-butylsalicylidene- Compounds of formulas (I / b) and (I / c) to (I / g) using enantioselective reduction catalysts such as 1,2-cyclohexanediaminomanganese (III) chloride, wherein R _2a and R _3a Together form an oxo group) as a pure enantiomer,

Compounds of formulas (I / a) to (I / h) that make up the complete compounds of the present invention that can be purified by conventional separation methods are optionally added with their pharmaceutically acceptable acids or bases. And isomers thereof, suitably according to conventional separation methods:

Where

R _a and R _b together with the nitrogen atom form a 5- or 6-membered heterocycle, which ring may contain, in addition to the nitrogen atom, another hetero atom selected from sulfur, oxygen and nitrogen,

R _c is a hydrogen atom or a group of formula (VI) Wherein R ₄ and R ₁ are as defined above, at least one compound of formula (V) contains a group of formula (VI),

R _2a and R _3a together form an oxo group or R _2a and R ₁ form an additional bond, in which case R _3a is an NR ′ _a R ′ _b group as defined above,

R ₁ and R ₄ are as defined above,

R ' ₆ is a linear or branched (C ₁ -C ₆ ) alkyl group,

X is hydrogen or a fluorine atom,

X 'is a hydrogen atom, _a group of -NR' _a R ' _b where R' _a and R ' _b may mean R _a and R _b respectively or a group of formula (iii) (Wherein R ' _a , R' _b , R ' ₁ and R' ₄ may mean R _a , R _b , R ₁ and R ₄ , respectively),

X '' is a hydrogen atom, _a -NR ' _a R' _b group as defined above or a group of formula (VII) (Wherein R ′ ₁ and R ′ ₄ may mean R ₁ and R ₄ , respectively),

X '' ′ is a hydrogen atom, _a —NR ′ _a R ′ _b group as defined above, or a group of formula (VII) (Wherein R ′ ₁ , R ′ _2a , R ′ _3a and R ′ ₄ may mean R ₁ , R _2a , R _3a and R ₄ , respectively),

X ′ '' in the compound of formula (I / h) is a hydrogen atom, _a -NR ' _a R' _b group as defined above or a group of formula (VII) Wherein R ' ₁ , R' ₂ , R ' ₃ and R' ₄ are as defined above,

Y ⁻ is, for example, para-toluenesulfonate or trifluoromethanesulfonate,

Y ^'- is a halogen anion or PF ₆ ^- is a group,

Y 'is a group ^{-, -} Y is the same as defined above ^- or Y'.

In addition to the novelty of the compounds of the present invention, they exhibit analgesic properties and properties that promote the recognition process, and because of these properties they can be combined with Alzheimer's disease, Parkinson's disease, Peak disease, Korsakoff disease, and prefrontal and subcortical dementia. There is a tendency to use it to treat pain and lowering of personality associated with neurodegenerative diseases and brain aging.

The invention also relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) and at least one suitable inert nontoxic excipient. In the pharmaceutical composition according to the present invention, more specifically, oral administration, parenteral administration (intravenous or subcutaneous administration) and non-administration, tablet or dragee, sublingual tablet, gelatin capsule, lozenges, suppositories, creams, ointments Mention may be made of suitable gels for skin, injectable preparations, drinkable suspensions and the like.

The dose used is adjusted according to the nature and severity of the disease, the route of administration, the age and weight of the patient. Doses vary from 0.01 mg to 1 g per day in one or more administrations.

The following examples are intended to illustrate the invention and are not intended to limit the invention.

The following preparation methods yield the compounds of the present invention, or synthetic intermediates useful for the preparation of the compounds of the present invention.

Preparation 1: 2-fluoro-1-methylpyridinium 4-methylbenzenesulfonate

10 mmol 2-fluoropyridine and 10 mmol methyl 4-methylbenzenesulfonate were mixed in a 50 ml round bottom flask and stirred at 70 ° C. for 6 hours under a nitrogen atmosphere. The resulting salt as a white solid was used without further purification in the next step.

Preparation 2: 1- (1-phenylvinyl) pyrrolidine

After heating 100 g of molecular sieve at 500 ° C. for 8 hours, a mixture of 22 mmol pyrrolidine and 20 mmol acetophenone in 200 ml of anhydrous ether was added. The reaction mixture, a ketone (C = 0 1689cm ^-1) is not observed any more in the enemy outside the supernatant, everywhere was stirred at room temperature until a maximum of the absorbance for the Min (C = CN 1600cm ^-1). The mixture was then filtered and the molecular sieve washed with ether. The solvent was evaporated under reduced pressure and the crude residue was distilled off under reduced pressure.

Boiling Point: 110 ℃ / 2mmHg

Preparations 3-11 were carried out in the same manner as in Preparation 2.

Preparation 3: 4- (1-phenylvinyl) morpholine

Boiling Point: 125 ℃ / 2mmHg

Preparation 4: 1- [1- (4-methylphenyl) vinyl] pyrrolidine

Boiling Point: 135 ℃ / 10mmHg

Preparation 5: 1- [1- (4-methoxyphenyl) vinyl] pyrrolidine

Boiling Point: 160 ℃ / 0.4mmHg

Preparation 6: 1- [1- (4-chlorophenyl) vinyl] pyrrolidine

Boiling Point: 125 ℃ / 10mmHg

Preparation 7: 1- [1- (4-bromophenyl) vinyl] pyrrolidine

Boiling Point: 160 ℃ / 0.3mmHg

Preparation 8: 1- [1- (4-fluorophenyl) vinyl] pyrrolidine

Boiling Point: 140 ℃ / 0.3mmHg

Preparation 9: 1- [1- (2-bromophenyl) vinyl] pyrrolidine

Boiling Point: 130 ℃ / 0.3mmHg

Preparation 10: 1- [1- (3-bromophenyl) vinyl] pyrrolidine

Boiling Point: 165 ℃ / 0.3mmHg

Preparation 11: 1- (1-cyclohexen-1-yl) pyrrolidine

1 g para-toluenesulfonic acid was added to a mixture of 22 mmol pyrrolidine and 20 mmol cyclohexanone in 200 ml dry benzene. The reaction mixture was stirred under reflux until the ketone disappeared in the infrared and at the same time enamine appeared. The solvent is then evaporated off and the crude residue is distilled off under vacuum.

Boiling Point: 110 ℃ / 15mmHg

Preparation 12: 1- (1-cyclohexen-1-yl) morpholine

Benzene was replaced with toluene and pyrrolidine was replaced with morpholine to carry out in the same manner as in Preparation 11.

Boiling Point: 140 ℃ / 15mmHg

Preparation 13: 2,6-difluoro-1-methylpyridinium trifluoromethanesulfonate

10 mmol of 2,6-difluoropyridine and 10 mmol of trifluoromethanesulfonic acid were mixed in a 50 ml round bottom flask, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The white solid obtained was used directly in the following reaction without further purification.

Preparation 14: 1- {1- [4- (dimethylamino) phenyl] vinyl} pyrrolidine

It was carried out in the same manner as in Preparation 2.

Preparation 15: 1- [1- (2-fluorophenyl) vinyl} pyrrolidine

It was carried out in the same manner as in Preparation 2.

Preparation 16: 1- {1- [4- (methylthio) phenyl] vinyl} pyrrolidine

It was carried out in the same manner as in Preparation 2.

Preparation 17: 1- {1- [4- (trifluoromethyl) phenyl] vinyl} pyrrolidine

It was carried out in the same manner as in Preparation 2.

Preparation 18: 2-fluoro-1-ethylpyridinium-4-methylbenzenesulfonate

It was carried out in the same manner as in Preparation 2.

Example 1: 1-methyl-2- [2- (4-methylphenyl) -2-oxoethyl] pyridinium hexafluorophosphate

20 mmol of the compound obtained in Preparation 1 were dissolved in 15 ml of anhydrous acetonitrile under nitrogen atmosphere, and 22 mmol of the compound obtained in Preparation 4 in 10 ml of acetonitrile were added dropwise at room temperature. The reaction mixture was stirred at 80 ° C. for 2 hours, making the solution red. The solvent was evaporated in vacuo and the viscous red residue was taken up in 30 ml of concentrated hydrochloric acid and heated under reflux for 3 hours. The dark brown solution obtained was cooled to room temperature and then 22 mmol of ammonium hexafluorophosphate was added. The precipitate obtained was filtered off, washed with cold water and ethyl acetate and recrystallized from ethanol.

Melting Point: 163-165 ℃

Elemental Trace Analysis:

C H N

% Theoretic 47.05 3.95 3.92

% Experimental Value 47.18 3.88 3.81

Example 2: 1-methyl-2- [2- (4-methylphenyl) -2-oxoethyl] pyridinium iodide

10 mmol of the compound obtained in Example 1 was dissolved in 35 ml of acetone, and 100 mg of 15 mmol of NaI were added in portions. Immediately a white precipitate was obtained and the mixture was stirred for 14 h at room temperature in a sealed tube. The white solid obtained was filtered off and washed with acetone.

Melting Point: 191-193 ℃

Elemental Trace Analysis:

C H N

% Theoretic 49.56 4.16 4.13

% Experiment 49.82 4.12 4.40

Examples 3 to 14 were carried out in the same manner as in Examples 1 and 2.

Example 3: 1-methyl-2- (2-oxo-2- (4-methoxyphenyl) ethyl) pyridinium hexafluorophosphate

Starting compound: Preparations 1 and 5

Melting Point: 168-170 ℃

Elemental Trace Analysis:

C H N

% Theorem 46.50 4.17 3.62

% Experimental Value 46.82 4.10 3.78

Example 4: 1-methyl-2- [2-oxo- (4-methoxyphenyl) ethyl] pyridinium iodide

Starting compound: Example 3

Melting Point: 214-216 ℃

Elemental Trace Analysis:

C H N

% Theoretic 47.78 4.37 3.79

% Experiment 48.67 4.68 4.02

Example 5: 1-methyl-2- [2-oxo-2- (4-chlorophenyl) ethyl] pyridinium hexafluorophosphate

Starting compound: Examples 1 and 6

Melting Point: 152-154 ℃

Elemental Trace Analysis:

C H N

% Theoretic 42.96 3.35 3.58

% Experiment 42.80 3.20 3.18

Example 5: 1-methyl-2- [2-oxo-2- (4-chlorophenyl) ethyl] pyridinium iodide

Starting compound: Example 5

Melting Point: 212-214 ℃

Elemental Trace Analysis:

C H N

% Theoretic 45.04 3.51 3.75

% Experimental Value 45.50 3.65 3.88

Example 7: 1-methyl-2- [2-oxo-2- (4-bromophenyl) ethyl] pyridinium hexafluorophosphate

Starting compound: Examples 1 and 7

Melting Point: 185-187 ℃

Elemental Trace Analysis:

C H N

% Theoretic 38.62 3.01 3.22

% Experiment 38.43 3.10 3.54

Example 8: 1-methyl-2- [2-oxo-2- (4-bromophenyl) ethyl] pyridinium iodide

Starting compound: Example 7

Melting Point: 222-224 ℃

Elemental Trace Analysis:

C H N

% Theoretical 40.30 3.14 3.36

% Experiment 40.46 3.30 3.26

Example 9: 1-methyl-2- (2-oxochlorohexyl) pyridinium hexafluorophosphate

Starting compound: Examples 1 and 11 or 12

Elemental Trace Analysis:

C H N

% Theoretic 42.97 4.81 4.18

% Experiment 43.21 4.76 4.01

Example 10 1-methyl-2- (2-oxocyclohexyl) pyridinium iodide

Starting compound: Example 9

Melting Point: 151-153 ℃

Elemental Trace Analysis:

C H N

% Theoretic 45.42 5.09 4.42

% Experimental Value 45.76 4.96 4.6

Example 11: 1-methyl-2- [2-oxo-2- (3-bromophenyl) ethyl] pyridinium hexafluorophosphate

Starting compound: Preparations 1 and 10

Example 12 1-methyl-2- [2-oxo-2- (3-bromophenyl) ethyl] pyridinium iodide

Starting compound: Example 11

Melting Point: 217-218 ℃

Elemental Trace Analysis:

C H N

% Theoretical 40.30 3.14 3.36

% Experiment 40.20 3.25 2.90

Example 13: 1-methyl-2- [2-oxo-2- (2-bromophenyl) ethyl] pyridinium hexafluorophosphate

Starting compound: Preparations 1 and 9

Example 14 1-methyl-2- [2-oxo-2- (2-bromophenyl) ethyl] pyridinium iodide

Starting compound: Example 13

Melting point: 204-205 ℃

Elemental Trace Analysis:

C H N

% Theoretical 40.30 3.14 3.36

% Experiment 40.26 3.32 3.04

Example 15a: 1-methyl-2- [2-oxo- (2-fluorophenyl) ethyl] pyridinium iodide

Starting from the compound obtained in Preparation 15, it was carried out in the same manner as in Examples 1 and 2.

Example 15b: 1- (2-fluorophenyl) -2- (1-methyl-2-piperidinyl) ethanone hydriodide

3 mmol of the compound obtained in Example 15a were dissolved in 150 ml of ethanol and 50 mg of platinum oxide was added all at once. Hydrogenation was carried out at an initial pressure of 5 atm at 24 ° C. If a theoretical capacity of hydrogen was observed (after about 3 hours), the catalyst was filtered off and washed with ethanol. The solvent was evaporated off and the residue obtained was recrystallized.

Melting point: 118-119 ℃

Examples 16-21 were carried out in the same manner as in Example 15b.

Example 16: 2- (1-methyl-2-piperidinyl) -1- (4-methoxyphenyl) -1-ethanone hydriodide

Initial Compound: Example 4

Melting Point: 201-203 ℃

Elemental Trace Analysis:

C H N

% Theoretic 47.99 5.91 3.73

% Experiment 48.10 6.01 3.45

Example 17: 2- (1-methyl-2-piperidinyl) -1- (4-chlorophenyl) -1-ethanone hydriodide

Initial Compound: Example 6

Melting point: 158-160 ℃

Elemental Trace Analysis:

C H N

% Theoretic 44.32 5.05 3.69

% Experimental Value 44.46 5.32 3.68

Example 18 2- (1-methyl-2-piperidinyl) -1- (4-bromophenyl) -1-ethanone hydriodide

Initial Compound: Example 8

Melting point: 182-184 ℃

Elemental Trace Analysis:

C H N

% Theoretic 39.72 4.53 3.31

% Experimental Value 39.81 4.60 3.54

Example 18a: (R) -2- (1-methyl-2-piperidinyl) -1- (4-bromophenyl) -1-ethanone hydrochloride

Oxalyl chloride solution in dry CH ₂ Cl ₂ (10 ml) was placed in an oven-dried 25 ml flask, degassed and filled with nitrogen. DMSO (10 mmol) was added dropwise via syringe at -50 to -60 ° C. Example 60 (2) solution (0.5 mmol) in CH ₂ Cl ₂ (5 ml) was added dropwise within 5 minutes and stirring continued for an additional 30 minutes. Triethylamine (30 mmol) was added and the solution stirred for 10 minutes and then warmed at room temperature. Thereafter, water was added to the reaction mixture, and the aqueous solution was extracted with CH ₂ Cl ₂ . The combined organic phases were dried (MgSO ₄ ) and concentrated. The residue was purified by flash column chromatography (silica gel, AcOEt-MeOH-NH ₄ OH) to give an unstable light yellow oil, which was immediately dissolved in HCl-ether solution to yield a white solid. This solid was recrystallized from MeOH-ether to give the pure title product.

Melting Point: 191-194 ℃

[α] = + 10 (c = 0.1; MeOH)

Example 18b: (S) -2- (1-methyl-2-piperidinyl) -1- (4-bromophenyl) -1-ethanone hydrochloride

The title product was obtained using the same method as Example 18a, starting from the compound of Example 60 (1).

Melting Point: 192-194 ℃

[α] = -9 (c = 0.1; MeOH)

Example 19 2- (1-methyl-2-piperidinyl) cyclohexanone hydriodide

Starting compound: Example 10

Melting Point: 160-162 ℃

Example 20 2- (1-methyl-2-piperidinyl) -1- (3-bromophenyl) -1-ethanone hydriodide

Starting compound: Example 12

Melting Point: 134-136 ℃

Elemental Trace Analysis:

C H N

% Theoretic 39.72 4.53 3.31

% Experimental Value 39.88 4.45 3.26

Example 21: 2- (1-methyl-2-piperidinyl) -1- (2-bromophenyl) -1-ethanone hydriodide

Starting compound: Example 14

Melting Point: 163.5-164 ℃

Elemental Trace Analysis:

C H N

% Theoretic 39.72 4.53 3.31

% Experimental Value 39.66 4.47 3.26

Example 22 1-methyl-2- [2-phenyl-2- (1-pyrrolidinyl) ethenyl] pyridinium hexafluorophosphate

20 mmol of the compound obtained in Preparation 1 were dissolved in 15 ml of dry acetonitrile under a nitrogen atmosphere. A solution of 22 mmol of the compound obtained in Preparation 2 in 10 ml of acetonitrile was added dropwise while stirring at room temperature. The reaction mixture was stirred for 14 hours at room temperature and then for 2 hours at 80 ° C. The solution turned red. The solvent was evaporated to dryness under reduced pressure, 30 ml of cool water was added, followed by the addition of 22 mmol of ammonium hexafluorophosphate in 20 ml of ethyl acetate / ether (1/1) to give a viscous red residue. Filter, wash with water and AcOEt / Et) (1/1) to afford pure title product.

Melting Point: 143-145 ℃

Elemental Trace Analysis:

C H N

% Theoretic 52.67 5.16 7.83

% Experimental Value 52.97 5.26 7.81

Example 23 1-methyl-2- [2-phenyl-2- (1-pyrrolidinyl) ethenyl] pyridinium iodide

The same method as in Example 2 was used.

Melting point: 200-202 ℃

Example 24 1-methyl-2- [20 (4-morpholinyl) -2-phenylethenyl] pyridinium hexafluorophosphate

The same method as in Example 22 was used.

Starting compound: Preparations 1 and 3

Melting Point: 168-170 ℃

Elemental Trace Analysis:

C H N

% Theoretic 50.71 4.96 6.57

% Experiment 50.68 4.88 6.44

Example 25 1-methyl-2- [2- (4-morpholinyl) -2-phenylethenyl] pyridinium iodide

The same process as in Example 2 was carried out.

Example 26 1-methyl-2- (4-morpholinyl) -6- [2- (4-morpholinyl) -2-phenylethenyl] -pyridinium hexafluorophosphate

20 mmol of the compound obtained in Preparation 13 were dissolved in 15 ml of dry acetonitrile under a nitrogen atmosphere. 22 mmol of the compound obtained in Preparation 3 and 22 mmol of morpholine were added, and the mixture was stirred at room temperature for 14 hours and at 80 ° C. for 2 hours. Thereafter, the product was carried out in the same manner as in Example 22.

Example 27 1-methyl-2- (4-morpholinyl) -6- [2- (4-morpholinyl) -2-phenylethenyl] -pyridinium iodide

It was carried out in the same manner as in Example 2.

Melting Point: 214-216 ℃

Example 28 1-methyl-2,6-bis (2-oxo-2-phenylethyl) pyridinium trifluoromethanesulfonate

20 mmol of the compound obtained in Preparation 13 were dissolved in 15 ml of dry acetonitrile. To 15 ml of acetonitrile, 44 mmol of the solution of the compound obtained in Preparation 2 were added dropwise at 0 ° C. while stirring under a nitrogen atmosphere. Thereafter, the reaction mixture was stirred for 14 hours at room temperature. The solution turned red; The solvent is then evaporated off and the viscous red residue obtained is taken up in 50 ml of concentrated hydrochloric acid and heated under reflux for 3 hours. After cooling to room temperature, the title compound crystallized in the form of white needles, filtered and washed with cold water and ethyl acetate.

Melting Point: 175 ℃

Elemental Trace Analysis:

C H N

% Theoretic 57.61 4.61 2.92

% Experimental 57.82 4.40 2.99

Example 29 1-methyl-2,6-bis (2-oxo-2-phenylethyl) pyridinium iodide

It was carried out in the same manner as in Example 2.

Melting point: 197-199 ℃

Elemental Trace Analysis:

C H N

% Theoretic 57.76 4.41 3.06

% Experimental 57.88 4.52 3.35

Example 30 2,6-bis [2- (4-bromophenyl) -2-oxoethyl] -1-methylpyridinium trifluoromethanesulfonate

It was carried out in the same manner as in Example 28.

Starting compound: Preparations 13 and 7

Example 31 2,6-bis [2- (4-bromophenyl) -2-oxoethyl] -1-methylpyridinium iodide

It was carried out in the same manner as in Example 2.

Example 32 1-methyl-2,6-bis (2-oxocyclohexyl) pyridinium hexafluorophosphate

20 mmol of the compound obtained in Preparation 13 dissolved in 15 ml of acetonitrile and 44 mmol of the compound obtained in Preparation 11 dissolved in 15 ml of acetone were added at 0 ° C. under a nitrogen atmosphere. The reaction mixture was warmed back to room temperature and stirred at 80 ° C. for 3 hours. The solution turned red and the solvent was evaporated under reduced pressure, then the residue was taken up in 50 ml of concentrated hydrochloric acid and heated under reflux for 3 hours. After cooling, the solution was filtered to remove all solid impurities and 22 mmol of NH ₄ PF ₆ were added. After extraction with ethyl acetate and drying over MgSO ₄ , the solvent is evaporated under reduced pressure and the solid obtained is recrystallized from ethanol / ethyl acetate mixture.

Elemental Trace Analysis:

C H N

% Theoretic 50.10 5.61 3.25

% Experiment 50.28 5.31 3.66

Example 33 1-methyl-2,6-bis (2-oxocyclohexyl) pyridinium iodide

It was carried out in the same manner as in Example 2.

Example 34 1-methyl-2- [2- (4-methylphenyl) -2-oxoethyl] -6- (2-oxo-2-phenylethyl) -pyridinium trifluoromethanesulfonate

20 mmol of the compound obtained in Preparation 13 dissolved in 15 ml of dry acetonitrile and 22 mmol of the compound obtained in Preparation 2 dissolved in 10 ml of acetonitrile were added dropwise at 0 ° C. under a nitrogen atmosphere. Then the reaction mixture was allowed to warm to room temperature and stirred for 3 hours at room temperature. After addition of 22 mmol of the compound obtained in Preparation 4 in 10 ml of acetonitrile, the reaction mixture was stirred for an additional 14 hours. The solvent is then evaporated off and the viscous red residue obtained is taken up in 50 ml of concentrated hydrochloric acid and heated under reflux for 3 hours. After cooling, the title compound crystallized in the form of a white nipple, which was filtered and washed successively with water and ethyl acetate.

Melting point: 188-190 ℃

Elemental Trace Analysis:

C H N

% Theoretic 58.40 4.50 2.84

% Experiment 58.54 4.76 2.78

Example 35 1-methyl-2- [2- (4-methylphenyl) -2-oxoethyl] -6- (2-oxo-2-phenylethyl) -pyridinium iodide

It was carried out in the same manner as in Example 2.

Melting point: 205-206 ℃

Elemental Trace Analysis:

C H N

% Theoretic 58.59 4.71 2.91

% Experiment 58.65 4.65 2.76

Examples 36-49 were performed in the same manner as in Examples 34 and 35.

Example 36 2- [2- (4-chlorophenyl) -2-oxoethyl] -1-methyl-6- (2-oxo-2-phenylethyl) -pyridinium trifluoromethanesulfonate

Starting compound: Preparations 13, 2 and 6

Melting point: 199-210 ℃

Example 37: 2- [2- (4-chlorophenyl) -2-oxoethyl] -1-methyl-6- (2-oxo-2-phenylethyl) -pyridinium iodide

Starting Compound: Example 36

Melting Point: 213-215 ℃

Example 38: 2- [2- (4-fluorophenyl) -2-oxoethyl] -1-methyl-6- (2-oxo-2-phenylethyl) -pyridinium trifluoromethanesulfonate

Starting compound: preparations 13, 2 and 8

Example 39: 2- [2- (4-fluorophenyl) -2-oxoethyl] -1-methyl-6- (2-oxo-2-phenylethyl) -pyridinium iodide

Starting Compound: Preparation 38

Melting point: 220-222 ℃

Example 40: 2- [2- (4-bromophenyl) -2-oxoethyl] -1-methyl-6- (2-oxo-2-phenylethyl) -pyridinium trifluoromethanesulfonate

Starting compound: Preparations 13, 2 and 7

Example 41: 2- [2- (4-bromophenyl) -2-oxoethyl] -1-methyl-6- (2-oxo-2-phenylethyl) -pyridinium iodide

Starting compound: Example 40

Melting Point: 218-220 ℃

Example 42: 2- [2- (4-bromophenyl) -2-oxoethyl] -6- [2- (4-chlorophenyl) -2-oxoethyl] -1-methylpyridinium trifluoromethane Sulfonate

Starting compound: Preparations 13, 6 and 7

Melting Point: 226-228 ℃

Example 43: 2- [2- (4-bromophenyl) -2-oxoethyl] -6- [2- (4-chlorophenyl) -2-oxoethyl] -1-methylpyridinium iodide

Starting compound: Example 42

Melting Point: 226-227 ℃

Example 44: 2- [2- (4-methoxyphenyl) -2-oxoethyl] -1-methyl-6- (2-oxo-2-phenylethyl) -pyridinium trifluoromethanesulfonate

Starting compound: preparations 13, 2 and 5

Melting Point: 193-195 ℃

Example 45: 2- [2- (4-methoxyphenyl) -2-oxoethyl] -1-methyl-6- (2-oxo-2-phenylethyl) -pyridinium iodide

Starting compound: Example 44

Melting Point: 203-205 ℃

Example 46: 2- [2- (4-fluorophenyl) -2-oxoethyl] -6- [2- (4-methoxyphenyl) -2-oxoethyl] -1-methylpyridinium trifluoro Methanesulfonate

Starting compound: preparations 13, 5 and 8

Melting Point: 208-210 ℃

Example 47: 2- [2- (4-fluorophenyl) -2-oxoethyl] -6- [2- (4-methoxyphenyl) -2-oxoethyl] -1-methylpyridinium iodide

Starting compound: Example 46

Melting Point: 219-220 ℃

Example 48: 2- [2- (4-methoxyphenyl) -2-oxoethyl] -1-methyl-6- [2- (4-methylphenyl) -2-oxoethyl] pyridinium trifluoromethanesulfo Nate

Starting compound: Preparations 13, 4 and 5

Example 49: 2- [2- (4-methoxyphenyl) -2-oxoethyl] -1-methyl-6- [2- (4-methylphenyl) -2-oxoethyl] pyridinium iodide

Starting Compound: Example 48

Example 50: 1- (4-methoxyphenyl) -2- {1-methyl-6- [2- (4-methylphenyl) -2-oxoethyl] -2-piperidinyl} -1-ethanone hydroxide Reiodide

After dissolving 3 mmol of the compound obtained in Example 49 in 150 ml of ethanol, 70 mg of platinum oxide was added in one portion. Hydrogenation was carried out at an initial pressure of 3 atm at 24 ° C. If a theoretical capacity of hydrogen was observed (after about 3 hours), the catalyst was filtered off and washed with ethanol. The solvent is then evaporated off and the title compound is obtained in the form of a white solid.

Examples 51-56 were performed in the same manner as in Example 50.

Example 51: 2- {1-methyl-6- [2- (4-methylphenyl) -2-oxoethyl] -2-piperidinyl} -1-phenyl-1-ethanone hydriodide

Starting compound: Example 35

Melting Point: 192-193 ℃

Example 52: 1- (4-chlorophenyl) -2- [1-methyl-6- (2-oxo-2-phenylethyl) -2-piperidinyl] -1-ethanone hydriodide

Starting compound: Example 37

Melting Point: 152-154 ℃

Example 53 1- (4-fluorophenyl) -2- [1-methyl-6- (2-oxo-2-phenylethyl) -2-piperidinyl] -1-ethanone hydriodide

Starting compound: Example 39

Melting Point: 152-154 ℃

Example 54: 1- (4-Bromophenyl) -2- {6- [2- (4-chlorophenyl) -2-oxoethyl] -1-methyl-2-piperidinyl} -1-ethanone Hydriodine

Starting Compound: Example 43

Melting point: 200-202 ℃

Example 55 1- (4-bromophenyl) -2- [1-methyl-6- (2-oxo-2-phenylethyl) -2-piperidinyl] -1-ethanone hydriodide

Starting Compound: Example 41

Example 56: 1- (4-Bromophenyl) -2- {6- [2- (4-bromophenyl) -2-oxoethyl] -1-methyl-2-piperidinyl} -1-eta Rice paddy hydriodine

Starting compound: Example 31

Example 57a: 2- {2- [4- (dimethylamino) phenyl] -2-oxoethyl} -1-methylpyridinium iodide

Starting from the compound obtained in Preparation 14, it was carried out in the same manner as in Examples 1 and 2.

Example 57b: 1- [4- (dimethylamino) phenyl] -2- (2-pyridinyl) ethanone

8 mmol of the compound obtained in Example 57a was added to 15 g of boiling pyridine hydrochloride and the turbid solution obtained was heated under reflux for 10 minutes. The hot reaction mixture was poured into 30 g of ice and 20 ml of ammonium hydroxide 37%. After cooling in an ice bath for about 2 hours, the title compound crystallized and the crystals were filtered off and washed with cold water.

Example 58: 1- (4-bromophenyl) -2- (2-pyridinyl) -1-ethanol

Step A: 1- (4-bromophenyl) -2- (2-pyridinyl) -1-ethanone

8 mmol of the compound obtained in Example 8 was added to 15 g of boiling pyridine hydrochloride and the turbid solution obtained was heated under reflux for 10 minutes. The hot reaction mixture was poured into 30 g of ice and 20 ml of ammonium hydroxide 37%. Upon cooling in an ice bath for about 2 hours, the title compound crystallized in the form of yellow green crystals which were filtered off and washed with cold water.

Step B: 1- (4-Bromophenyl) -2- (2-pyridinyl) -1-ethanol

1 mmol of the compound obtained in step A dissolved in 15 ml of ethanol and 1.5 mmol of NaBH ₄ were added in two portions. After the reaction mixture was stirred for 3 hours, the reaction was stopped using 0.5 ml of acetic acid; The mixture with 10% NaOH was basic and extracted with dichloromethane (3 × 15 ml). The organic phase was dried over MgSO ₄ , evaporated and the solid obtained was recrystallized from ethanol.

Example 58a: S-(-) 1- (4-bromophenyl) -2- (2-pyridinyl) -1-ethanol

A solution of NaBH ₄ (1.51 g, 40 mmol) modified with ethanol (2.34 ml) and tetrahydrofurfuryl alcohol (20 ml) in CHCl ₃ (40 ml) in (R, R) in CHCl ₃ (30 ml) under nitrogen atmosphere at −20 ° C. Dropwise was added dropwise to the (-)-(-)-jacobcin MnCl catalyst (420 mg) and the compound solution (8.28 g, 30 mmol) obtained in step A of Example 58. The reaction was monitored by TLC and upon completion the reaction was stopped by the addition of saturated NH ₄ Cl solution (15 ml). The aqueous solution was extracted with CH ₂ Cl ₂ , the extract was dried and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate-petroleum ether) to afford the title compound.

Melting Point: 161-162 ℃

[α] = -34 (c = 1, CHCl ₃ )

Elemental Trace Analysis:

C H N

% Theoretic 56.14 4.35 5.04

% Experimental 56.25 4.06 4.99

Example 58b: R-(+)-1- (4-Bromophenyl) -2- (2-pyridinyl) -ethanol

The title product was obtained in the same manner as in Example 58a using (S, S)-(+)-Jacobsen MnCl catalyst.

Melting Point: 161-162.5 ℃

[α] = + 34 (c = 1, CHCl ₃ )

Elemental Trace Analysis:

C H N

% Theoretic 56.14 4.35 5.04

% Experimental 56.25 4.06 4.99

Example 59: 1- (4-bromophenyl) -2- (2-piperidinyl) -1-ethanol

1 mmol of the compound obtained in Example 58 was dissolved in 20 ml of acetic acid and 8 mg of platinum oxide was added. The hydrogenation was carried out starting at an initial pressure of 3 atm at 24 ° C. After 3 hours of reaction, the catalyst was filtered off and washed with dichloromethane. The solvent was distilled off and the obtained residue was dissolved in 10% sodium hydroxide solution and extracted with dichloromethane. The organic phase was washed with water, dried over MgSO ₄ and evaporated to afford the title compound in the form of a white solid.

Example 60 1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol

Starting from the compound obtained in Example 18, it was carried out in the same manner as in Step B of Example 58.

Example 60 (1): (S, S)-(-)-1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol

To the compound (1 mmol) obtained in Example 58a in acetic acid (20 ml) was added platinum oxide (20 mg) and the solution was hydrogenated at 5 ° C. at 5 atm. After removal of the catalyst and solvent, dichloromethane and aqueous sodium carbonate are added, washed, and the organic phase is dried and then evaporated to give (S, S)-(-)-4'-bromo-norcedamine and (R, A mixture of two stereoisomers of S)-(1) -4'-bromo-noralosedamine was provided. Recrystallization from ethyl acetate / petroleum ether (1: 1) yielded the S, S-isomer of pure 1- (4-bromophenyl) -2- (2-piperidinyl) ethanol, which was acetonitrile (25 ml). ) And aqueous formaldehyde (37%, 25 ml). Then sodium cyanoborohydride (25 ml) was added. The mixture was stirred for 1 hour at room temperature and acetic acid was added. After 20 minutes, the solution is neutralized with aqueous sodium hydroxide, extracted with dichloromethane, the extract is dried, evaporated and the residue is purified by silica gel chromatography (recrystallized from ethyl acetate-petroleum ether 1: 1). The title product was obtained.

Melting point: 102-104 ℃

[α] =-28 (c = 1, EtOH)

Elemental Trace Analysis:

C H N

% Theoretic 56.38 6.76 4.70

% Experimental 56.72 6.66 5.01

Example 60 (2): (R, R)-(+)-1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol

Starting with the compound obtained in Example 58b, the title compound was obtained in the same manner as in Example 60 (1).

Melting point: 102-104 ℃

[α] = + 28 (c = 1, EtOH)

Elemental Trace Analysis:

C H N

% Theoretic 56.38 6.76 4.70

% Experimental 56.81 6.82 4.76

Example 61a: 2- {2- [4- (methylthio) phenyl] -2-oxoethyl} -1-methylpyridinium iodide

Starting from the compound obtained in Preparation 16, it was carried out in the same manner as in Examples 1 and 2.

Example 61b: 1- [4- (methylthio) phenyl] -2- (2-pyridinyl) ethanone

Starting from the compound obtained in Example 61a, it was carried out in the same manner as in Example 57b.

Melting Point: 118-119.5 ℃

Example 62: 1-methyl-2- [2- (4-chlorophenyl) -2-hydroxyethyl] pyridinium iodide

Starting from the compound obtained in Example 6, it was carried out in the same manner as in Step B of Example 58.

Melting Point: 172-173.5 ℃

Example 63 1-methyl-2- {2-hydroxy-2- [4- (methylthio) phenyl] ethyl} pyridinium iodide

Starting from the compound obtained in Example 61a, it was carried out in the same manner as in Step B of Example 58.

Melting Point: 145-148 ℃

Example 64: 2- {2- [4- (dimethylthio) phenyl] -2- (2-pyridinyl) ethanol

Starting from the compound obtained in Example 57a, it was carried out in the same manner as in Step B of Example 58.

Example 65 1- [4- (methylthio) phenyl] -2- (2-pyridinyl) ethanol

Starting from the compound obtained in Example 61b, it was carried out in the same manner as in Step B of Example 58.

Example 66a: 1-methyl-2- {2-oxo-2- [4- (trifluoromethyl) phenyl] ethyl} pyridinium iodide

Starting from the compound obtained in Preparation 17, it was carried out in the same manner as in Examples 1 and 2.

Example 66b: 2- (2-pyridinyl) -1- [4- (trifluoromethyl) phenyl] ethanol

Step A: 2- (2-pyridinyl) -1- [4- (trifluoromethyl) phenyl] ethanone

Starting from the compound obtained in Example 66a, it was carried out in the same manner as in Example 57b.

Step B: 2- (2-pyridinyl) -1- [4- (trifluoromethyl) phenyl] ethanol

Starting from the compound obtained in step A, it was carried out in the same manner as in step B of Example 58.

Melting Point: 156-158 ℃

Example 67 1- (2-fluoromethyl) -2- (2-pyridinyl) ethanol

Starting from the compound obtained in Example 15a, it was carried out in the same manner as in Example 66b.

Melting point: 71-73 ℃

Example 68 1- (3-bromophenyl) -2- (2-pyridinyl) ethanol

Starting from the compound obtained in Example 12, it was carried out in the same manner as in Example 66b.

Melting point: 82-84 ℃

Example 69 1- (2-bromophenyl) -2- (2-pyridinyl) ethanol

Starting from the compound obtained in Example 14, it was carried out in the same manner as in Example 66b. oil.

Example 70: 2- (2-piperidinyl) -1- [4- (trifluoromethyl) phenyl] ethanol

Starting from the compound obtained in Example 66b, the same procedure as in Example 59 was performed.

Melting point: 95-98 ℃

Example 71 1- (4-chlorophenyl) -2- (1-methyl-2-piperidinyl) ethanol

Starting from the compound obtained in Example 17, it was carried out in the same manner as in Step B of Example 58.

Melting point: 84-87 ℃

Example 72: 2- (1-methyl-2-piperidinyl) -1- [4- (trifluoromethyl) phenyl] ethanol

Starting from the compound obtained in step A of example 66b, it was carried out in the same manner as in step B of example 58.

Example 73: 2- [2- (4-bromophenyl) -2-oxoethyl] -1-ethylpyridinium chloride

The title compound was obtained in the same manner as in Example 1 starting from Preparations 1 and 7 without adding ammonium hexafluorophosphate.

Melting point: 112-114 ℃

Example 74: 2- [2- (4-bromophenyl) -2-hydroxyethyl] -1-methylpyridinium chloride

Starting from the compound of Example 8, it was carried out in the same manner as in Step B of Example 58.

Melting point: 64-65 ℃

Pharmacological Study of Compounds of the Invention

Example A: Acute Toxicity Study

Acute toxicity was evaluated after oral administration to each group containing 8 mice (26 ± 2 grams). Animals were observed at regular intervals during the course of the first day of treatment and were observed daily for two weeks. LD ₅₀ (the dose at which 50% of the animals result in lethality) was evaluated and the low toxicity of the present invention was demonstrated.

Example B: Abdominal Contraction Induced by Phenyl-p-benzoquinone (PBQ) in NMRI Mice

Intraperitoneal administration of alcohol solution in PBQ induced abdominal cramps in mice (SIEGMUND et al., Proc. Soc. Exp. Biol., 1957, 95, 729-731). This spasm is characterized by repeated contraction of the abdominal muscles by the elongation of the hind legs. Most analgesics antagonize these abdominal cramps (COLLIER et al., Brit. J. Pharmacol. Chem., 1968, 32, 295-310). When t = 0, animals were weighed and the compound to be studied was administered intraperitoneally. Control animal groups were provided with a solvent used for the compound. At t = 30 minutes, PBQ (0.2%) alcohol solution was administered intraperitoneally at a dose of 0.25 ml / mouse. Immediately after administration of PBQ, the animals were placed in a cylinder of flexislas (L = 19.5; I.D. = 5 cm). From t = 35 minutes to t = 45 minutes, the responses of the animals were observed and the total number of abdominal cramps per animal was recorded. Results are expressed as% inhibition of the number of abdominal cramps measured in control animals at the active dose of the compound studied.

The results obtained show an inhibition rate of 30 to 90% for low active doses, which demonstrates the analgesic properties of the compounds of the present invention.

Example C: Social Recognition in Wistar Rats

The social cognition test, initially described by THOR and HOLLOWAY (J. Comp. Physiol., 1982, 96, 1000-1006) in 1982, was later published by many authors to study the memory recognition effects of new compounds. (DANTZER et al., Psychopharmacology, 1987, 91, 363-368; PERIO et al., Psychopharmacology, 1989, 97, 262-268). The test is based on the general expression of olfactory memory in mice and the general tendency to forget them, and memory is assessed by the recognition of the same kind of young mice by adult mice. Randomly taken young rats (21 days old) were placed in cages containing adult rats for 5 minutes. As a result of the video observation, social cognitive behaviors of adult rats were observed and their overall duration was measured. The young mice were then removed from the adult rat cages and placed in individual cages until a second introduction was made. Compounds were injected into adult mice, and after 2 hours, young mice were added again (5 minutes). Thereafter, social cognitive behavior was observed and this duration was measured. The evaluation criterion is the difference in seconds between "recognition" time in two encounters (T ₂ -T ₁ ).

The results obtained showed a difference (T ₂ -T ₁ ) of -20s to -45s for doses of 0.3 to 3 mg / kg, which means that the compounds of the present invention greatly enhance the gearing force at low doses. do.

Example D: Object Recognition in Wistar Rats

The object recognition test of Wistar rats was initially developed by ENNACEUR and DELACOUR (Behav. Brain Res., 1988, 31, 47-59). The test is based on the animal's natural exploration activity, which is characterized by human foot memory. These memory tests include aging (SCALI et al., Eur. J. Pharmacol., 1997, 325, 173-180) and cholinergic dysfunction (BARTOLINI et al., Pharm. Biochem. Behav. 1996, 53 (2), 277 Sensitive to the exploration differences of two very similar types of objects, one familiar and the other new. Before the test, animals were allowed to get used to the environment (without things). In the first session, mice were locked in two identical objects (3 minutes). The exploration period was evaluated for each object. 24 hours later, in the second session (three minutes), one of the two things was replaced with a new one. The exploration period for each object was evaluated. The criterion is the difference in seconds between the exploration time for two new objects and the exploration time for familiar objects in the second session course (deltas). Control animals pre-intraperitoneally administered the carrier 30 minutes prior to each session exhibited the same propensity for familiar and new objects, indicating that they had forgotten the first introduced. Animals treated with this compound that enhance memory awareness primarily explored new objects, meaning that they were still remembering the first introduced.

The results obtained showed a difference (delta) of 5 s to 10 s for a dose of 0.03 to 3 mg / kg, meaning that the compounds of the present invention greatly enhance memory at low doses.

Example E: Pharmaceutical Compositions

Formulations for the preparation of 1000 tablets each comprising 10 mg of the following active ingredients:

2- (1-methyl-2-piperidinyl) -1- (4-bromophenyl)

-1-Ethanone hydriodide (Example 18) ------------------------ 10 g

Hydroxypropyl cellulose ------------------------------------ 2g

Wheat starch ------------------------------------------------ ------ 10g

Lactose ------------------------------------------------- ------ 100 g

Magnesium Stearate ---------------------------------------- 3g

Talc ------------------------------------------------- -------- 3g

The compounds of the present invention were very effective in improving analgesia and memory.

Claims (18)

Compounds of formula (I), enantiomers, diastereomers thereof, or addition salts with pharmaceutically acceptable acids or bases: Where A is a pyridine group, a pyridinium group or a piperidine group, R ₂ is a hydrogen atom, R ₃ is a hydroxy group, or R ₂ and R ₃ together form an oxo group, R ₄ is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted heteroaryl group, R ₁ is a hydrogen atom, or R ₁ and R ₄ together with two carbon atoms form a ring of 6 carbon atoms, or R ₁ and R ₂ form an additional bond, in which case R ₃ represents a heterocycle A 5- or 6-membered heterocycle containing nitrogen atoms to which it is bound and which may contain another hetero atom selected from sulfur, oxygen and nitrogen, R ₅ is a 5- or 6-membered heterocyclic ring of formula (II) which contains a nitrogen atom which binds the hetero ring to ring A and may contain another hetero atom selected from sulfur, oxygen and nitrogen (Wherein R ' ₁ , R' ₂ , R ' ₃ and R' ₄ may be the same as R ₁ , R ₂ , R ₃ and R ₄ , respectively) or a hydrogen atom and R ₅ is hydrogen, ₄ may not be an unsubstituted phenyl group, an unsubstituted naphthyl group or a heteroaryl group, R ₆ is a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group, R ₆ is present or absent depending on the nature of the ring A, Heteroaryl is understood to represent aromatic monocyclic or bicyclic 5- to 10-membered groups containing 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, The term "substituted" as used for "phenyl", "naphthyl" or "heteroaryl", refers to a linear or branched (C ₁ -C ₆ ) alkyl, linear or branched (C ₁ -C ₆ ) group. Same or selected from alkoxy, mercapto, linear or branched (C ₁ -C ₆ ) alkylthio, amino, linear or branched (C ₁ -C ₆ ) alkylamino, di- (C ₁ -C ₆ ) alkylamino It is understood that it may be substituted by one or more groups which may be different, wherein each alkyl moiety is a linear or branched (C ₁ -C ₆ ) polyhaloalkyl, hydroxy or halogen atom; When R ₂ and R ₃ together form an oxo group, R ₅ is a hydrogen atom, R ₆ is a hydrogen atom or absent, and R ₄ is hydroxy, alkoxy, CF ₃ and halogen (if A is a piperidine group) , Bromine is excluded) or a group other than a phenyl group substituted by one group selected from hydroxy and alkoxy, When R ₂ is a hydrogen atom, R ₃ is a hydroxy group, R ₅ is a hydrogen atom, R ₆ is a hydrogen atom or absent, R ₄ is hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, Groups other than linear or branched (C ₁ -C ₆ ) alkyl and phenyl groups substituted by one group selected from chlorine or substituted by several groups selected from hydroxy and alkoxy, The compound of formula (I) may not be 1- (1,3-benzodioxol-5-yl) -2- (2-pyridinyl) ethanol or 2- (2-pyridinyl) cyclohexanone. The method of claim 1, wherein Is a piperidinyl group or an N-methylpiperidinyl group, an enantiomer, diastereoisomer thereof, or an addition salt with a pharmaceutically acceptable acid or base. The method of claim 1, wherein Is a pyridinyl group or an N-methylpyridinium group, an enantiomer, diastereomer thereof, or an addition salt with a pharmaceutically acceptable acid or base. 2. Compounds of formula (I), enantiomers, diastereomers, or addition salts with pharmaceutically acceptable acids or bases thereof according to claim 1, characterized in that R ₄ is a substituted phenyl group. 2. Compounds of formula (I), enantiomers, diastereomers, or addition salts with pharmaceutically acceptable acids or bases thereof according to claim 1, characterized in that R ₅ is a hydrogen atom. 2. Compounds of formula (I), enantiomers, diastereomers, or addition salts with pharmaceutically acceptable acids or bases thereof according to claim 1, characterized in that R ₅ is a group of formula (II). 2. Compounds of formula (I), enantiomers, diastereomers, or addition salts with pharmaceutically acceptable acids or bases thereof according to claim 1, characterized in that R ₂ and R ₃ together form an oxo group . The method of claim 1, wherein, R is ₂ is a hydrogen atom, a compound of formula (Ⅰ), characterized in that R ₃ is a hydroxy group, addition salts and its enantiomers, diastereomers, or acids or bases pharmaceutically acceptable . 2. Compounds of formula (I) according to claim 1, characterized in that 1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanone, enantiomers thereof, Diastereomers, or addition salts with pharmaceutically acceptable acids or bases. A compound of formula (I) according to claim 1, characterized in that (R) -2- (1-methyl-2-piperidinyl) -1- (4-bromophenyl) -1-ethanone Addition salts with pharmaceutically acceptable acids or bases thereof. A compound of formula (I) according to claim 1, characterized in that (S) -2- (1-methyl-2-piperidinyl) -1- (4-bromophenyl) -1-ethanone Addition salts with pharmaceutically acceptable acids or bases thereof. The compound of formula (I) according to claim 1, characterized in that it is 1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol, enantiomer, part thereof Stereoisomers, or addition salts with pharmaceutically acceptable acids or bases. A compound of formula (I) according to claim 1, characterized in that (S, S) -1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol, Or addition salts thereof with pharmaceutically acceptable acids or bases. A compound of formula (I) according to claim 1, characterized in that (R, R) -1- (4-bromophenyl) -2- (1-methyl-2-piperidinyl) -1-ethanol, Or addition salts thereof with pharmaceutically acceptable acids or bases. The compound of formula (I) according to claim 1, or a pharmaceutically thereof, which is 1-methyl-2- [2-oxo-2- (4-bromophenyl) ethyl] pyridinium iodide Addition salts with acceptable acids or bases. A process for preparing the compound of formula (I) according to claim 1, Using a compound of formula (III) as an starting material and alkylating with an alkylating agent such as, for example, alkyl para-toluenesulfonate or alkyl trifluoromethanesulfonate to obtain a compound of formula (IV); The compound of formula (IV) is reacted with one or two compounds of formula (V) which may be the same or different to give a compound of formula (I / a) which is a specific form of the compound of formula (I) Can do it; Compounds of formula (I / a) can be treated with hydrochloric acid such as HCl, HBr or HI or ammonium salts such as NH ₄ ⁺ PF ₆ ^- to give compounds of formula (I / a '); The compound of formula (I / a ') may be hydrolyzed with concentrated hydrochloric acid solution to obtain a compound of formula (I / b), which is a specific form of the compound of formula (I); The compounds of formulas (I / a), (I / a ') and (I / b) constitute compounds of formula (I / c), which are certain forms of compounds of formula (I); Converting the compound of formula (I / c) to the corresponding iodide salt by the action of NaI to obtain a compound of formula (I / d), which is a specific form of the compound of formula (I); Compounds of formula (I / d) can be subjected to, for example, catalytic hydrogenation on platinum oxide to give compounds of formula (I / e) which are specific forms of compounds of formula (I), or to pyridinium salts. Treating to obtain a compound of formula (I / f) which is a specific form of a compound of formula (I); Hydrogenating the obtained compound by a catalytic hydrogenation reaction to obtain a compound of formula (I / g) which is a specific form of the compound of formula (I); Compounds of formulas (I / b) and (I / c) to (I / g), wherein R _2a and R _3a together form an oxo group, are treated with a reducing agent such as, for example, NaBH ₄ , It is possible to obtain the following general formula (I / h), which is a specific form of the compound of I); Compounds of formula (I / h) may be selected from (R, R)-(-) or (S, S)-(+)-N, N'-bis (3,5-di-tert-butylsalicylidene- Compounds of formulas (I / b) and (I / c) to (I / g) using enantioselective reduction catalysts such as 1,2-cyclohexanediaminomanganese (III) chloride, wherein R _2a and R _3a Together form an oxo group) as a pure enantiomer, Compounds of formulas (I / a) to (I / h) that make up the complete compounds of the present invention that can be purified by conventional separation methods are optionally added with their pharmaceutically acceptable acids or bases. And isomers thereof, suitably according to conventional separation methods: Where R _a and R _b together with the nitrogen atom form a 5- or 6-membered heterocycle, which ring may contain, in addition to the nitrogen atom, another hetero atom selected from sulfur, oxygen and nitrogen, R _c is a hydrogen atom or a group of formula (VI) Wherein R ₄ and R ₁ are as defined above, at least one compound of formula (V) contains a group of formula (VI), R _2a and R _3a together form an oxo group or R _2a and R ₁ form an additional bond, in which case R _3a is an NR ′ _a R ′ _b group as defined above, R ₁ and R ₄ are as defined above, R ' ₆ is a linear or branched (C ₁ -C ₆ ) alkyl group, X is hydrogen or a fluorine atom, X 'is a hydrogen atom, _a group of -NR' _a R ' _b where R' _a and R ' _b may mean R _a and R _b respectively or a group of formula (iii) (Wherein R ' _a , R' _b , R ' ₁ and R' ₄ may mean R _a , R _b , R ₁ and R ₄ , respectively), X '' is a hydrogen atom, _a -NR ' _a R' _b group as defined above or a group of formula (VII) (Wherein R ′ ₁ and R ′ ₄ may mean R ₁ and R ₄ , respectively), X '' ′ is a hydrogen atom, _a —NR ′ _a R ′ _b group as defined above, or a group of formula (VII) (Wherein R ′ ₁ , R ′ _2a , R ′ _3a and R ′ ₄ may mean R ₁ , R _2a , R _3a and R ₄ , respectively), X ′ '' in the compound of formula (I / h) is a hydrogen atom, _a -NR ' _a R' _b group as defined above or a group of formula (VII) Wherein R ' ₁ , R' ₂ , R ' ₃ and R' ₄ are as defined above, Y ⁻ is, for example, para-toluenesulfonate or trifluoromethanesulfonate, Y ^'- is a halogen anion or PF ₆ ^- is a group, Y 'is a group ^{-, -} Y is the same as defined above ^- or Y'. 16. The at least one compound of formula (I) according to any one of claims 1 to 15 or an addition salt thereof with a pharmaceutically acceptable acid or base thereof, together with at least one pharmaceutically acceptable excipient Pharmaceutical composition comprising. 18. The method according to claim 17, for use in the manufacture of a medicament for the treatment of memory loss and pain associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Peak disease, Korsakoff disease, and prefrontal and subcortical dementia and brain aging. Composition.